The work proposed is based on the principal investigator's previous studies in connection with this Program[unreadable] Project and recent preliminary data obtained related to the progression of vascular dysfunction during the[unreadable] aging process. Our results allowed us to conclude that the vascular dysfunction observed with aging, is[unreadable] characterized by a progressive reduction in the synthesis and/or bioavailability of nitric oxide (NO), resulting[unreadable] in or caused by an increased oxidant stress in endothelial cells. Significant differences in the regulation by[unreadable] endothelial mediators of skeletal muscle and coronary vessel function were also found in endothelial nitric[unreadable] oxide synthase knockout (eNOS-KO) mice as well as type 2 diabetic (db/db) mice. The aim of our work[unreadable] proposed is to evaluate to what extent the effects of aging of blood vessels is accelerated with[unreadable] cardiovascular disorders and whether aging of blood vessels may provide an additional risk factor for[unreadable] adverse cardiovascular events. These issues will be studied in two models of metabolic syndrome of[unreadable] different etiology, namely type 2 diabetic mice and eNOS.KO mice. In this project we plan to test the[unreadable] hypothesis that the effects of NADPH oxidase-derived oxidants, superoxide and hydrogen peroxide, and[unreadable] their interactions with nitric oxide, on the function of coronary and skeletal muscle resistance vessels during[unreadable] the process of aging, is the primary cause of the development of vascular dysfunction. Specific Aim 1 is to[unreadable] investigate altered mediation of responses to dilator and constrictor agents, pressure and flow of resistance[unreadable] vessels with aging. Specific Aim 2 is to study the progression of metabolic syndrome with aging. These[unreadable] studies will involve measurements of metabolic and hormonal parameters, as well as gene expression in[unreadable] blood vessels during aging. Finally in Specific Aim 3 we aim to elucidate the role of reactive oxidant species[unreadable] on altered regulation of blood vessels with aging, as well as localization of oxidants by state-of-the-art[unreadable] imaging methods. These studies will lead to a better understanding of the causes of age related vascular[unreadable] dysfunction and the pathogenesis of metabolic syndrome, suggesting novel therapeutic targets for the[unreadable] prevention or treatment of these conditions.[unreadable]